ENST00000373294.8:c.1A>G

Variant names:

• chrX-80022270-A-G
• ENST00000373294.8:c.1A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000373294.8(TBX22):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: TBX22 ENST00000373294.8 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54

Genes affected

TBX22 (HGNC:11600): (T-box transcription factor 22) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Mutations in this gene have been associated with the inherited X-linked disorder, Cleft palate with ankyloglossia, and it is believed to play a major role in human palatogenesis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 94 codons. Genomic position: 80023164. Lost 0.179 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX22	NM_001109878.2	c.1A>G	p.Met1?	start_lost, splice_region_variant	Exon 2 of 9	ENST00000373296.8	NP_001103348.1
TBX22	NM_016954.2	c.1A>G	p.Met1?	start_lost	Exon 1 of 8		NP_058650.1
TBX22	NM_001109879.2	c.-356A>G		splice_region_variant	Exon 2 of 9		NP_001103349.1
TBX22	NM_001109879.2	c.-356A>G		5_prime_UTR_variant	Exon 2 of 9		NP_001103349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX22	ENST00000373294.8	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	1		ENSP00000362390.5
TBX22	ENST00000373296.8	c.1A>G	p.Met1?	start_lost, splice_region_variant	Exon 2 of 9	5	NM_001109878.2	ENSP00000362393.3
TBX22	ENST00000476373.1	n.122A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 2	3
TBX22	ENST00000626498.2	n.1A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 9	2		ENSP00000487527.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TBX22-related disorder Uncertain:1

Nov 04, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TBX22 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T;T
FATHMM_MKL	Benign	0.71	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.46	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.64
Sift	Benign	0.43	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.30	B;B
Vest4		0.89
MutPred		0.95		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP		0.99
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.37
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-79277769;